Neuropathy is a disease caused by structural or functional abnormalities of the nervous system. The nervous system is divided into the central nervous system which is distributed in the brain and the spinal cord and involved in controlling their functions, and the peripheral nervous system which is distributed in almost all organs excluding the brain and the spinal cord and involved in controlling their functions. The peripheral nervous system is subdivided into the motor nervous system, the sensory nervous system, the autonomic nervous system. A peripheral nerve, where neurites branch out beyond the brain and the spinal cord to the body, arms, and legs, transmits sensation felt at arms and legs to the central nerve (brain and spiral cord), and transmits orders of the central nerve to muscles.
The peripheral nerve can be injured by various causes, which is called collectively as the peripheral neuropathy. The mono-neuropathy refers to a case in which a single peripheral nerve is injured, and the multiple neuropathy refers to a case in which many peripheral nerves are injured to a similar level. The mono-neuropathy usually occurs when a single peripheral nerve is abnormally pressed or traumatically injured during extending to ends of arms and legs. The mono-neuropathy can be treated with operations.
The multiple neuropathy can be induced by various causes, such as metabolic diseases (e.g., diabetes, renal failure, hypothyroidism), drugs (e.g., antitumor agents, antituberculosis drugs) or toxic substance intoxication (e.g., Pb, organic solvents), mal-nutrition (e.g., vitamin deficiency, alcoholism), connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus), inflammatory diseases (Guillain-Barre syndrome), or genetically determined neuropathy. In addition, the multiple neuropathy can be caused by cancers.
Until now, the neuropathy has been treated with drugs used as a symptomatic therapy that improves symptoms only and there are almost no fundamental remedies for the neuropathy. Only epalrestat, an aldose reductase inhibitor, was approved by US Food and Drugs Administration (FDA), with respect to diabetic peripheral neuropathy, one of the multiple neuropathies, but epalrestat is not used due to its low therapeutic effects (Foster D W., Harrison's Principles of Internal Medicine 13, p 1979, 1999; Stephen L D, Applied Therapeutics: the clinical use of drugs. 6, p 48.1-48.62, 1996).
Meanwhile, a protein that affects the growth, differentiation, and survival of neurons in the central nervous system (CNS) and the peripheral nervous system (PNS) is called collectively as a neurotrophic factor (NF), which is one of neuron control factors that regulate the growth, differentiation, and death of neurons. Examples of the NF include a brain-induced neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4, and NT-5. These NFs are synthesized at different areas, and have different differentiation, different expression, and different target regions.
A nerve growth factor (NGF), one of the NFs, inhibits the degeneration and death of neurons so as to prevent a decrease in the number of neurons, to protect neurons from damages, and to retain mature neuron sources (Hefti F., J. Neurosci., 6(8), pp 2155-2162, 1986; and Levi-Montalcini R., et al., Proc. Natl. Acad. Sci. USA, 46, pp 384-391, 1960). It is known that when the nervous system normally develops, about 50% of neurons on growth are removed by cell death (Raff M C., et al., Science, 262(5134), pp 695-70, 1993), and that NGFs secreted by a target cell determine survival of neurons. In order for neurons to survive, grow, and differentiate in a normal state, a growth factor, such as the NGF, is necessarily required.
Such feasibility of the NGF has led development of a recombinant human nerve growth factor in order to treat a diabetic neuropathy, one of the multiple neuropathies. However, the recombinant human nerve growth factor is still unsatisfactory in safety and efficacy (Apfel S C et al., Journal of American Medical Association 284(17), pp 2215-2221, 2000).